Phosphoinositide 3-kinases (PI3K) are lipid kinases that phosphorylate lipids at the 3-hydroxyl residue of an inositol ring (Whitman et al (1988) Nature, 332:664). The 3-phosphorylated phospholipids (PIP3s) generated by PI3-kinases act as second messengers recruiting kinases with lipid binding domains (including plekstrin homology (PH) regions), such as Akt and phosphoinositide-dependent kinase-1 (PDK1). Binding of Akt to membrane PIP3s causes the translocation of Akt to the plasma membrane, bringing Akt into contact with PDK1, which is responsible for activating Akt. The tumor-suppressor phosphatase, PTEN, dephosphorylates PIP3 and therefore acts as a negative regulator of Akt activation. The PI3-kinases Akt and PDK1 are important in the regulation of many cellular processes including cell cycle regulation, proliferation, survival, apoptosis and motility and are significant components of the molecular mechanisms of diseases such as cancer, diabetes and immune inflammation (Vivanco et al (2002) Nature Rev. Cancer 2:489; Phillips et al (1998) Cancer 83:41).
The main PI3-kinase isoform in cancer is the Class I PI3-kinase, p110 α (alpha) (U.S. Pat. No. 5,824,492; U.S. Pat. No. 5,846,824; U.S. Pat. No. 6,274,327). Other isoforms are implicated in cardiovascular and immune-inflammatory disease (Workman P (2004) Biochem Soc Trans 32:393-396; Patel et al (2004) Proceedings of the American Association of Cancer Research (Abstract LB-247) 95th Annual Meeting, March 27-31, Orlando, Fla., USA; Ahmadi K and Waterfield M D (2004) Encyclopedia of Biological Chemistry (Lennarz W J, Lane M D eds) Elsevier/Academic Press). The PI3 kinase/Akt/PTEN pathway is an attractive target for cancer drug development since such modulating or inhibitory agents would be expected to inhibit proliferation, reverse the repression of apoptosis and surmount resistance to cytotoxic agents in cancer cells (Folkes et al (2008) J. Med. Chem. 51:5522-5532; Yaguchi et al (2006) Jour. of the Nat. Cancer Inst. 98(8):545-556). The PI3K-PTEN-AKT signaling pathway is deregulated in a wide variety of cancers (Samuels Y, Wang Z, Bardellil A et al. High frequency of mutations of the PIK3CA gene in human cancers. (2004) Science; 304 (5670):554; Carpten J, Faber A L, Horn C. “A transforming mutation in the pleckstrin homology domain of AKT1 in cancer” (2007) Nature; 448:439-444).
GDC-0980 (Genentech, Inc., Roche, RG-7422) demonstrates broad activity in preclinical xenograft cancer models; breast, ovarian, lung, and prostate, and is being developed for the potential oral treatment of cancer including solid tumors and non-Hodgkin's lymphoma (Wagner A J; Burris III HA; de Bono J S et al AACR-NCI-EORTC International Congress (2009), 21st:November 17 (Abs B137) “Pharmacokinetics and Pharmacodynamic biomarkers for the dual PI3K/mTOR inhibitor GDC-0980: initial phase I evaluation”; U.S. Pat. No. 7,888,352; US 2009/0098135; US 2010/0233164). In March 2009, a phase I trial in patients with solid tumors or NHL was initiated; in April 2009, a second phase I trial began; these trials were ongoing in April 2010. In December 2010, a phase Ib combination trial in metastatic breast cancer was initiated. In July 2010, a phase II trial in metastatic breast cancer was planned for the first half of 2011; patients would receive GDC-0980 combined with hormonal therapy. Clinical results to date suggest that GDC-0980 may benefit patients with solid tumors or hematological malignancies. (Sutherlin D P, Belvin M, Bao L et al, American Association for Cancer Research Annual Meeting, (2011) 102nd:April 04 (Abs 2787)).
GDC-0980 is a potent, selective, oral inhibitor of Class I PI3K and mTOR kinase with the following in vitro biochemical IC50s against Class I isoforms of PI3K: p110α (alpha) 4.8 nM; p110β (beta) 26.8 nM; p110 (gamma) 13.8 nM; p110d (delta) 6.7 nM; mTOR Ki 17.3 nM. GDC-0980 was selective for PI3K versus a large panel of kinases (>145), including other members of the phosphatidylinositol kinase family. In PC3 and MCF7-neo/HER2 cell lines, the compound demonstrated IC50 values of 307 and 320 nM, respectively. GDC-0980 was stable in human microsomes and hepatocytes, exhibited low activity against hERG IC50>100 μM (microM) and did not elicit significant responses in a receptor screening assay (n=68; GDC-0980=10 microM). Moderate-to-high clearance was observed in rodents (60 ml/min/kg) and dogs (12 ml/min/kg). The terminal half-life of the compound was 6 to 18 h, with dose-proportional increases in AUC and Cmax values following a single oral dose. GDC-0980 (25 to 150 mg/kg qd po) was efficacious across multiple xenograft models, including mouse PC3 PTEN-prostate and MCF7.1 E545K breast xenograft models. In a MDA-MB-361.1 breast cancer xenograft model, GDC-0980 produced significant growth inhibition at a minimum dose of 1.0 mg/kg QD.